Alzheimer's disease (AD) is a progressive neurological disease that results in cognitive deterioration, reduces quality of life, and is a significant economic burden on society. The need for symptomatic treatments of AD- associated cognitive impairment is high and is likely to remain high because: discovery of a cure is likely fa in the future; millions of people are already afflicted by the disease; and difficulties in early diagnosis will continue to result in individuals with cognitive impairment. Unfortunately, availabl treatments are minimally effective and often produce adverse side effects. The long-term goal is to identify drugs to treat AD-related cognitive impairment. The first step in achieving that long-term goal is to establish an appropriate animal model for screening candidate pharmacotherapeutics. We will use APPswe/PS1dE9 mice, which are a transgenic mouse model of AD, trained to perform two cognitive tasks: a short-term memory task and an attention task. Both tasks are modeled after tasks used in humans to assess cognitive function. The objective of this application is to determine the profile of short-term memory and attention deficits in APPswe/PS1dE9 mice (i.e., how age, testing frequency, and difficulty level affect the development and expression of cognitive deficits). Our central hypothesis is that APPswe/PS1dE9 mice will develop increasing deficits in short-term memory and attention over their lifespan, that deficits will appear at earlier ages in animals tested intermittently versus continuously, and that deficits will appear at earlier ages under occasional high difficulty conditions versus routine conditions. The rationale for the proposed research is that a detailed understanding of the cognitive deficit profile in these mice will guide the design of future evaluations of potential pharmacotherapeutics to treat AD-associated cognitive impairment. We will achieve the objective of this proposal by pursuing two specific aims: 1) Determine the profile of age-related changes in short-term working memory in APPswe/PS1dE9 mice; and 2) Determine the profile of age-related changes in attention in APPswe/PS1dE9 mice. The research is significant because it is expected to advance the development of pharmacotherapeutics for AD-associated cognitive impairment by providing a clinically relevant, laboratory-based, performance baseline against which therapeutic efficacy can be evaluated. Ultimately, such knowledge has the potential to improve quality of life for AD patients and reduce the costs associated with their care. Additionally, the proposed project will provide a unique opportunity for students to participate in psychopharmacology and neuroscience research and will improve the research environment at Texas Tech University.